title: PRMT5 is upregulated in malignant and metastatic melanoma and regulates expression of MITF and p27(Kip1.).
abstract: Protein arginine methyltransferase-5 (PRMT5) is a Type II arginine methyltransferase that regulates various cellular functions. We hypothesized that PRMT5 plays a role in regulating the growth of human melanoma cells. Immunohistochemical analysis indicated significant upregulation of PRMT5 in human melanocytic nevi, malignant melanomas and metastatic melanomas as compared to normal epidermis. Furthermore, nuclear PRMT5 was significantly decreased in metastatic melanomas as compared to primary cutaneous melanomas. In human metastatic melanoma cell lines, PRMT5 was predominantly cytoplasmic, and associated with its enzymatic cofactor Mep50, but not STAT3 or cyclin D1. However, histologic examination of tumor xenografts from athymic mice revealed heterogeneous nuclear and cytoplasmic PRMT5 expression. Depletion of PRMT5 via siRNA inhibited proliferation in a subset of melanoma cell lines, while it accelerated growth of others. Loss of PRMT5 also led to reduced expression of MITF (microphthalmia-associated transcription factor), a melanocyte-lineage specific oncogene, and increased expression of the cell cycle regulator p27(Kip1). These results are the first to report elevated PRMT5 expression in human melanoma specimens and indicate this protein may regulate MITF and p27(Kip1) expression in human melanoma cells.
authors.affiliation: Department of Internal Medicine, Division of Medical Oncology, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio, United States of America.
authors.forename: Courtney
authors.initials: C
authors.lastname: Nicholas
authors.forename: Jennifer
authors.initials: J
authors.lastname: Yang
authors.forename: Sara B
authors.initials: SB
authors.lastname: Peters
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Bill
authors.forename: Robert A
authors.initials: RA
authors.lastname: Baiocchi
authors.forename: Fengting
authors.initials: F
authors.lastname: Yan
authors.forename: Saïd
authors.initials: S
authors.lastname: Sïf
authors.forename: Sookil
authors.initials: S
authors.lastname: Tae
authors.forename: Eugenio
authors.initials: E
authors.lastname: Gaudio
authors.forename: Xin
authors.initials: X
authors.lastname: Wu
authors.forename: Michael R
authors.initials: MR
authors.lastname: Grever
authors.forename: Gregory S
authors.initials: GS
authors.lastname: Young
authors.forename: Gregory B
authors.initials: GB
authors.lastname: Lesinski
mesh_terms: D000818:Animals; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism; D004817:Epidermis / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D006801:Humans; D007150:Immunohistochemistry; D008545:Melanoma / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D051739:Microphthalmia-Associated Transcription Factor / Q000378:metabolism*; D009362:Neoplasm Metastasis / Q000473:pathology*; D011484:Protein-Arginine N-Methyltransferases / Q000378:metabolism*
chemical_list: C497234:MITF protein, human; D051739:Microphthalmia-Associated Transcription Factor; D050760:Cyclin-Dependent Kinase Inhibitor p27; C400529:PRMT5 protein, human; D011484:Protein-Arginine N-Methyltransferases